Method for the synthesis of substituted formylamines and substituted amines

ABSTRACT

An improved method for the synthesis of substituted formylamines and substituted amines via an accelerated Leuckart reaction. The Leuckart reaction is accelerated by reacting formamide or N-alkylformamide and formic acid with an aldehyde or a ketone at a preferred molar ratio that accelerates the reaction. The improved method is applicable to various substituted aldehydes and ketones, including substituted benzaldehydes. An accelerated method for the hydrolysis of substituted formylamines into substituted amines using acid or base and a solvent at an elevated temperature. The improved method is useful for the accelerated synthesis of agrochemicals and pharmaceuticals such as vanillylamine, amphetamine and its analogs, and formamide fungicides.

This application claims benefit of 60/962,739, filed Jul. 31, 2007.

BACKGROUND OF THE INVENTION

Aldehydes and ketones are valuable building blocks for chemicalindustry. Reductive amination is a fundamental chemistry process thatdramatically expands the application of aldehydes and ketones bytransforming them into amines. The Leuckart reaction is a unique onestep method of reductive amination. It is a remarkably simple processthat includes only two components: the carbonyl compound and formamide.The reaction is completed simply by heating the components at 160° C. to185° C. for 6 to 25 hours [1]. The long processing time seemed to be theonly shortcoming of the reaction. However, it is associated with anumber of serious practical problems.

First, the prolonged exposure of the reaction mixture to hightemperatures inevitably leads to significant thermal decomposition ofthe components, and, consequently, to lower yields of the products anddifficulties with their isolation and purification. Second, maintaininghigh temperatures for a long period of time means high consumption ofenergy and increasing production costs which make the Leuckart reactionunattractive to chemical industry. Third, long processing times per seare unattractive to fast paced modern synthetic applications, such ascombinatorial chemistry and automated parallel synthesis. Thus, theLeuckart reaction as a unique one step method of reductive aminationbecame almost completely abandoned in modern synthetic chemistry.

Most of the current reductive amination procedures are currentlyperformed as two step combinations of the separate amination andreduction reactions. These two step procedures can often take as muchtime as the traditional Leuckart reaction [2]. They are also quiteexpensive because they require either the use of custom complexhydrides, or precious metal catalysts and high pressure equipment. Theironly advantage over the one step Leuckart reaction is that they are notaccompanied by thermal decomposition and as a result produce cleanerproducts.

Therefore, it is evident that there is a compelling need for a fast andinexpensive method of reductive amination of aldehydes and ketonesequally attractive to industrial and laboratory practices.

SUMMARY OF THE INVENTION

An improved method for the synthesis of substituted formylamines via anaccelerated Leuckart reaction. The method may also include anaccelerated hydrolysis of the substituted formylamines to substitutedamines. The accelerated Leuckart reaction is conducted by reactingformamide or N-alkylformamide, formic acid and an aldehyde or a ketoneat a specific molar ratio and a specific temperature. The acceleratedLeuckart reaction is completed within minutes or seconds instead ofhours. The accelerated hydrolysis is conducted in the presence of aspecific acid and a specific solvent at an elevated temperature. Theaccelerated hydrolysis is also completed within seconds.

DETAILED DESCRIPTION OF INVENTION

The improved method of reductive amination of aldehydes and ketones viaan accelerated Leuckart reaction is an unanticipated discovery. TheLeuckart reaction was first described in the XIX century, and since thattime remained one of the slowest reactions in organic chemistry. Manyattempts were made to improve the reaction by using various additives,most commonly formic acid. However, the only area of improvementappeared to be the yield of the product, not the processing time.

In 1996 a significantly shorter reaction time of 30 minutes was achievedthrough the use of microwave heating [3]. However, the technique wassuccessfully applied only to a very narrow group of compounds. Inaddition, the current technical solutions for microwave assistedsynthesis do not allow for processing large-scale reactions andtherefore cannot be used in industry.

In the present invention using the Leuckart reaction it was unexpectedlydiscovered that the reaction time can be dramatically decreased bydecreasing the concentration of the aldehyde or a ketone used in thereaction. Certain specific molar ratios of the aldehyde (ketone), formicacid, and formamide (alkylformamide) the reaction time can be reduced to30 minutes or lower without the use of microwave assistance.Surprisingly it was found, that in many cases the reaction becomesinstant i.e. fully completed at the moment when it reaches the usualreaction temperature of 160-185° C. The accelerated Leuckart reaction isequally successful if it is conducted with conventional or microwaveheating.

The unique molar ratio of formamide (N-alkylformamide) to an aldehyde ora ketone is between 150:1 to 5:1 and most preferably between 100:1 to10:1. The specific molar ratio of formamide (N-alkylformamide) to formicacid is between 20:1 to 6:1 and most preferably 10:1.

The specific temperature of the accelerated Leuckart reaction is between150-200° C., and most preferably 180-190° C., if the reaction isconducted in an open system. It was found that the specific temperatureof the accelerated Leuckart reaction is between 150 to 250° C., mostpreferably 190-210° C., if the reaction is conducted in a sealed system.

This accelerated Leuckart reaction can be successfully applied to theareas where the traditional Leuckart reaction was not successful.Specifically, it was believed that the Leuckart reaction does not workon substituted benzaldehydes, and that the substituted benzylaminescannot be obtained from the respective benzaldehydes via the Leuckartreaction [1]. Further the accelerated Leuckart reaction does work onsubstituted benzaldehydes and that practically any substitutedbenzylamine can be prepared via the accelerated Leuckart reaction.Specifically, it was found that the reductive amination of vanillin(4-hydroxy-3-methoxybenzaldehyde) can be completed instantly via theaccelerated Leuckart reaction. Vanillylamine is an important industrialchemical that is used for the synthesis of safe natural painkillers,such as capsaicin and analogs. The new accelerated Leuckart reactioncomprises the new method of the synthesis of vanillylamine. Further, itwas also discovered that the accelerated Leuckart reaction can besuccessfully applied to α,β-unsaturated aldehydes and ketones, thuscomprising a new method of obtaining substituted allylamines.

The improved increased reaction rate prevents any substantial thermaldeterioration of the reaction mixture. As a result, the filtratesobtained after the separation of the reaction products can be repeatedlyused as solvents for the next rounds of the reaction. The acceleratedLeuckart reaction allows for the recycling of the reaction filtratesthus leading to quantitative yields of the products and minimal amountsof wastes.

As a complementary process, it was shown that substituted formylaminesthat are obtained as a result of the Leuckart reaction can be hydrolyzedto substituted amines via an accelerated (instant) hydrolysis. Normally,the hydrolysis step that follows the Leuckart reaction is a relativelyslow step that takes about an hour. Surprisingly, in the presence of aspecific solvent the hydrolysis step also becomes an instant procedure.As a result, the entire process of obtaining amines from aldehydes andketones becomes a combination of two accelerated (instant) reactions, anaccelerated (instant) Leuckart reaction and accelerated (instant)hydrolysis.

The present invention is illustrated by the following examples herein.

EXAMPLE 1 Reductive Amination of Vanillin (I)

The multi-mode MARS 5 reaction system (CEM Corporation) with GreenChemreaction vessels was used for the synthesis of vanillylformamide (II).1.52 g (10 mmol) of I, 20 ml of formamide, and 1 ml of formic acid wereplaced in the GreenChem reaction vessel. The GreenChem reaction vesselwas placed into the MARS 5 reaction system and the reaction mixture wasquickly heated to 200° C. The reaction mixture was kept at 200° C. for 3minutes and then cooled to 100° C. The GreenChem reaction vessel wasremoved from the MARS 5 system, the residual pressure was released, andthe reaction vessel was opened. TLC showed that the reaction wascomplete. The reaction mixture was diluted with 50 ml of water andextracted with ethyl acetate. The extract was dried with sodium sulfateand the solvent was evaporated. The residue was purified by columnchromatography (silica gel, CH₂Cl₂:CH₃OH 20:1 v/v) and yielded 1.37 g(75%) of N-vanillylformamide (II), m.p. 83.5° C. (benzene). ¹H NMR(D6-acetone): 8.21 s (1H, HC═O), 7.60 s (1H, NH), 7.55 br.s. (1H, OH),6.93 s (1H, aromatic), 6.76 s (2H, aromatic), 4.32 d (2H, CH₂), 3.80 s(3H, CH₃). ¹³C NMR (D6-acetone): 161.9 (C═O), 148.7, 147.1, 131.7,121.6, 116.1, 112.6 (aromatic carbons), 56.6 (CH₃), 42.3 (CH₂). IR (neatcrystals, ATR, cm⁻¹): 3296 (NH), 3213 (OH), 1643 (C═O). C₉H₁₁NO₃,calculated, %: C, 59.66; H, 6.12; N, 7.73. Found, %: C 59.90, 59.89; H6.13, 6.12; N 7.74, 7.73.

The reaction was repeated with 4.56 g (30 mmol) of vanillin and areaction time of 1 min. TLC showed that the reaction was complete. Thereaction mixture was extracted and purified the same way producing 3.29g (60%) of N-vanillylformamide (II).

The reaction was repeated with 1.52 g (10 mmol) of vanillin andconventional heating at 190° C. for 1 minute. The reaction mixture wasextracted and purified the same way producing 1.46 g (80%) ofN-vanillylformamide (II).

EXAMPLE 2 Instant Reductive Amination of 4-hydroxybenzaldehyde (III)

4-hydroxybenzaldehyde (1.22 g or 10 mmol), formamide (22.72 g or 20.03mL) and formic acid (2.43 g or 2 mL) were placed into a 50 mL roundbottom flask equipped with a thermometer, a reflux condenser, a magneticstirrer and a heating mantle. The reaction mixture was heated to 189° C.The heating was immediately turned off; the reaction flask was quicklyraised from the heating mantle and allowed to cool to room temperature.The TLC conducted on the cold reaction mixture confirmed that thereaction was complete. The reaction mixture was diluted with 50 ml ofwater and extracted with ethyl acetate. The extract was dried withsodium sulfate and the solvent was evaporated to produce 1.17 g (77.1%)of 4-hydroxybenzylformamide (IV).

EXAMPLE 3 Reductive Amination of1-(2,4-dichlorophenyl)-4,4-dimethyl-1-propen-3-one (V)

One g (3.9 mmol) of V, 2 ml of formic acid, and 20 ml of formamide wereplaced in a round bottom flask equipped with thermometer, refluxcondenser, and a heating mantle. The reaction mixture was heated to188-190° C. and maintained at this temperature for 10 minutes. Thereaction mixture was left to cool to room temperature overnight. Theprecipitated crystals were separated by filtration, rinsed with water,and dried with vacuum, producing 70% ofN-[1-(2,4-dichlorophenyl)-4,4-dimethyl-1-propen-3-yl]-formamide (VI).

EXAMPLE 4 Reductive Amination of Benzophenone (VII)

The reaction procedure for V was repeated with 5 g of benzophenone andthe reaction time of 15 minutes. The reaction produced 95% ofbenzhydrylformamide (VIII) (isolated yield).

EXAMPLE 5 Instant Hydrolysis ofN-[1-(2,4-dichlorophenyl)-4,4-dimethyl-1-propen-3-yl]formamide (VI)

One g of VI, 10 ml of concentrated hydrochloric acid, and 10 ml ofmethanol were placed in the GreenChem reaction vessel. The GreenChemreaction vessel was placed into the MARS 5 reaction system and thereaction mixture was quickly heated to 120° C. The microwave heating wasimmediately turned off and the reaction mixture was quickly cooled to60° C. The GreenChem reaction vessel was removed from the MARS 5 system,the residual pressure was released, and the reaction vessel was opened.TLC showed that the reaction was complete. The reaction mixture wascooled to room temperature; the precipitated crystals were separated byfiltration. The filtrate was dried with vacuum and produced anadditional amount of the product. The yield ofN-[1-(2,4-dichlorophenyl)-4,4-dimethyl-1-propen-3-yl]-aminehydrochloride (IX) is quantitative.

EXAMPLE 6 Instant Hydrolysis of Benzhydrylformamide (VIII)

The reaction procedure for VI was repeated with 1 g of VIII and producedquantitative yield of benzhydrylamine hydrochloride (X).

EXAMPLE 7 Instant Hydrolysis of Vanillylformamide (II)

The reaction procedure for VI was repeated with 1 g of II and producedquantitative yield of vanillylamine hydrochloride (Xi).

EXAMPLE 8 Reductive Amination of 2,4,6-trimethoxybenzaldehyde (XII) withRecycling of the Filtrate

1.96 g (10 mmol) of XII, 20 ml of formamide, and 2 ml of formic acidwere placed in the GreenChem reaction vessel. The GreenChem reactionvessel was placed into the MARS-5 reaction system and the reactionmixture was quickly heated to 200° C. The reaction mixture was kept at200° C. for 3 minutes and then cooled to 100° C. The GreenChem reactionvessel was removed from the MARS 5 system, the residual pressure wasreleased, and the reaction vessel was opened. TLC showed that thereaction was complete. The reaction mixture was cooled to roomtemperature; the precipitated crystals were separated by filtration,rinsed with water and dried with vacuum. The filtrate was used assolvent in the next reaction. The reaction was repeated 10 times. Thetotal of 9.6492 g of formic acid, and 34.5680 g of formamide were addedto the reaction mixture over the ten cycles to compensate the losses.The total yield of 2,4,6-trimethoxybenzylformamide (XIII) isquantitative.

Other Embodiments

The description of the specific embodiments of the invention ispresented for the purpose of illustration. It is not intended to beexhaustive nor to limit the scope of the invention to the specific formsdescribed herein. Although the invention has been described withreference to several embodiments, it will be understood by one ofordinary skill in the art that various modifications can be made withoutdeparting from the spirit and the scope of the invention, as set forthin the claims. All patents, patent applications and publicationsreferenced herein are hereby incorporated by reference.

Other embodiments are within the claims.

1. A method for the accelerated reductive amination of a substitutedbenzaldehyde into a substituted benzylformamide via an acceleratedLeuckart reaction, comprising: a. mixing a formic acid at a 1:20 to 1:6molar ratio to a formamide; b. mixing the aldehyde or a ketone at a1:100 to 1:10 molar ratio to the formamide; c. step a and step b are notorder dependent; d. raising temperature of said mixture to a reactiontemperature of at least 180° C.; and e. maintaining the mixture at thereaction temperature for a time between 0 to 30 minutes.
 2. The methodof claim 1, wherein the formamide is an unsubstituted formamide or aN-alkylformamide.
 3. The method of claim 2, wherein the N-alkylformamideis selected from a group consisting of N-methylformamide andN-ethylformamide.
 4. The method of claim 1, wherein the system is anopen system and the reaction temperature of the Leuckart reaction israised to between 180° C. and 190° C.
 5. The method of claim 1 whereinthe system is a sealed system and the reaction temperature of theLeuckart reaction is raised to between 190° C. and 210° C.
 6. The methodof claim 1, wherein the temperature of the Leuckart reaction is raisedor maintained by conventional heating or by microwave heating.
 7. Themethod of claim 1, wherein the substituted benzylformamide isvanillylformamide, 4-hydroxybenzylformamide, and2,4,6-trimethoxybenzylformamide.
 8. The method of claim 1, wherein thesubstituted benzaldehyde is vanillin, 4-hydroxybenzaldehyde, and2,4,6-trimethoxybenzaldehyde.
 9. The method of claim 1, furthercomprising an accelerated hydrolysis of the substituted benzylformamideinto a substituted benzylamine.